Nationwide Incidence and Clinical Outcomes of COVID-19 Vaccination-Related Myocarditis in Korea

Vaccine-related myocarditis (VRM) is a rare complication of COVID-19 vaccination. Prior large cohort and epidemiologic studies suggest higher risk with mRNA vaccines, especially in young males, typically within 7 days after the second dose. Reported incidences vary (approximately 1.4–5.0 per 100,000 vaccinated), and most cases are described as mild with favorable short-term outcomes, although fulminant myocarditis and deaths have been reported. To minimize selection and reporting bias and provide robust nationwide estimates, the Korea Disease Control and Prevention Agency (KDCA) established a national adverse event reporting system. This study analyzed the nationwide incidence and clinical outcomes of COVID-19 VRM in the entire vaccinated Korean population.

The study references multiple large-scale analyses: an Israeli cohort estimating myocarditis incidence of 2.13 per 100,000 after mRNA vaccination; U.S. VAERS data identifying 1,626 VRM cases among 192 million mRNA vaccine recipients; and population-based cohort studies in Denmark and the UK/USA evaluating risks of myocarditis/pericarditis post-vaccination versus SARS-CoV-2 infection. Prior literature consistently associates higher VRM risk with mRNA vaccines, young males, and after the second dose, with most cases described as mild. Nevertheless, case reports have documented fulminant myocarditis, cardiogenic shock requiring ECMO, and sudden cardiac death. The authors also discuss strengths and limitations of passive (e.g., VAERS) versus the KDCA’s legally mandated reporting with expert adjudication, and the Brighton Collaboration criteria for myocarditis diagnosis.

Design and setting: Retrospective nationwide analysis of all vaccinated individuals in Korea from 26 February to 31 December 2021. Ethical approval: KDCA IRB (2022-03-07-PE-A). Data collection and reporting: The KDCA established the COVID-19 Vaccination Task Force Adverse Event Investigation Team. Adverse events could be reported by medical institutions, vaccinees, or guardians via KDCA platforms. Myocarditis/pericarditis was designated a special adverse event with legal mandatory reporting by physicians. Epidemiologic investigators gathered medical records. An Expert Adjudication Committee (cardiologists, infectious disease, epidemiologists, regional investigators, KDCA officials) reviewed all suspected myocarditis/pericarditis cases. Case definition: Acute myocarditis within 42 days post-vaccination was considered COVID-19 VRM. The Committee employed the Brighton Collaboration (BC) myocarditis case definition but excluded BC level 3 cases, BC level 2 without elevated cardiac troponin, and cases with positive SARS-CoV-2 infection. Other potential causes (viral serologies, autoimmune markers) were evaluated where available. Clinical assessment: Initial and serial daily cardiac troponin measurements were obtained until normalization. ECG, echocardiography, cardiac magnetic resonance (CMR), and endomyocardial biopsy were reviewed when available. Severity definition: Severe VRM was defined as requiring ICU admission, fulminant myocarditis (FM), use of extracorporeal membrane oxygenation (ECMO), death, or heart transplantation. Vaccines and doses: Vaccinated cohort included recipients of ChAdOx1, BNT162b2, mRNA-1273, and Ad26.COV2.S; analyses considered dose order (first, second, third) and heterologous schedules (ChAdOx1→BNT162b2; mRNA-1273→BNT162b2). Statistical analysis: Continuous variables summarized as mean (SD) or median (IQR) and compared using Student’s t-test or Mann–Whitney U test. Categorical variables compared with chi-square or Fisher’s exact tests. Kaplan–Meier analysis estimated cumulative incidence up to 42 days after the last dose. ROC analyses identified cut-offs for age and systolic blood pressure (SBP) predicting severe VRM. Binary logistic regression identified independent predictors of severe VRM (variables with P < 0.1 in univariate and clinically relevant variables entered). Two-tailed tests; P < 0.05 considered significant. Software: SPSS v21.0 and R v4.2.1.

- Population: 44,276,704 individuals ≥12 years received ≥1 vaccine dose (ChAdOx1: 11,156,646; BNT162b2: 24,828,152; mRNA-1273: 6,781,796; Ad26.COV2.S: 1,510,110). Second doses in 41,084,830; third doses in 18,411,821. - Confirmed VRM: 480 of 1,533 suspected cases were adjudicated as VRM. - Overall incidence: 1.08 per 100,000 vaccinated persons (95% CI 0.99–1.19). - By sex: Males 1.35 vs females 0.82 per 100,000 (P < 0.001). - By vaccine type: mRNA vaccines 1.46 (95% CI 1.33–1.60) vs non-mRNA 0.14 (95% CI 0.08–0.23) per 100,000 (P < 0.001). - By age/sex: Highest in males 12–17 years: 5.29 (95% CI 4.06–6.78) per 100,000; males 18–29 years: 2.93 (95% CI 2.42–3.52); lowest in females ≥70 years: 0.16 (95% CI 0.05–0.38) per 100,000. - By dose: First dose 0.47; second dose 0.55; third dose 0.24 per 100,000. No difference between first and second; third significantly lower than first or second. - Dose by sex: First dose similar men vs women (0.47 vs 0.47 per 100,000; P = 1.000); second dose higher in men (0.76) vs women (0.31) per 100,000 (P < 0.001). - Heterologous schedules: ChAdOx1→BNT162b2: 8 VRM among 1,789,915 (0.45 per 100,000; 95% CI 0.19–0.88); mRNA-1273→BNT162b2: none among 98,761. - Laboratory/imaging: Troponin elevated in 464/480 (96.7%); remaining 16 confirmed by biopsy or CMR. ECG available in 322 (67.1%): abnormal in 218 (67.7%), most commonly ST elevation (134; 41.6%); sustained VT/VF in 16 (5.0%). Echo available in 285 (59.4%): LVEF <50% in 66 (23.2%). CMR in 78 (16.3%): myocarditis-compatible in 61 (72.7%); LVEF <50% in 26 (33.3%); LGE in 54 (69.2%). - Severity and outcomes: Severe VRM in 95 (19.8%): ICU 85 (17.7%), FM 36 (7.5%), ECMO 21 (4.4%), deaths 21 (4.4%), heart transplantation 1 (0.2%). Among FM, 21/36 (58.3%) required ECMO; 13/36 (36.1%) died (9 on ECMO). Third-dose VRM: 44 cases (9.2% of VRM); severe 4 (9.1%), ICU 4 (9.1%), FM 2 (4.6%), deaths 2 (4.6%). - Sudden cardiac death: 8 autopsy-confirmed SCDs attributable to VRM; all within 1 week post-vaccination, all <45 years, all mRNA recipients. - Predictors of severe VRM: On multivariate analysis, SBP <100 mmHg and age >40 years independently predicted severe VRM. Severe cases more often female, older, with dyspnea/fever, and lower BP at presentation.

This nationwide analysis shows that COVID-19 vaccine-related myocarditis is rare in Korea (1.08 per 100,000) and predominantly associated with mRNA vaccines, with highest incidence in adolescent and young adult males. However, unlike several prior reports describing largely mild clinical courses, 19.8% of cases were severe, including fulminant myocarditis, ECMO support, and death. The identification of eight autopsy-proven sudden cardiac deaths, all in individuals under 45 years after mRNA vaccination, highlights SCD as a critical albeit rare complication warranting careful monitoring and risk communication. Epidemiologic patterns differed somewhat from prior studies (e.g., weaker male predominance, less difference between first and second doses, notable cases in ages 40–60), possibly reflecting differences in vaccine use, risk period definitions, ethnicity, and—importantly—reporting systems. The KDCA’s legally mandated reporting with expert adjudication and compensation framework may have reduced underreporting and misclassification compared with passive systems like VAERS. The incidence and severity of VRM were lower after third doses compared to first or second doses, suggesting dose-order effects or evolving risk in the vaccinated population. Overall, the findings support ongoing surveillance, particularly in younger mRNA vaccine recipients, and emphasize early recognition of severe presentations (e.g., hypotension) to improve outcomes.

COVID-19 vaccine-related myocarditis in Korea was rare (1.08 per 100,000 vaccinated) and mainly associated with mRNA vaccines, especially in young males. Although many cases had favorable short-term courses, nearly one-fifth met severe criteria, including fulminant myocarditis and death. All eight autopsy-confirmed sudden cardiac deaths occurred within a week after mRNA vaccination in individuals under 45 years. Vigilant monitoring for severe VRM, including SCD, is warranted, particularly in younger populations receiving mRNA vaccines. Future research should clarify mechanisms (including hypersensitivity), refine risk stratification, and evaluate long-term outcomes, while comparing surveillance and adjudication methodologies across countries.

- Potential underestimation of VRM incidence despite mandatory reporting, given inherent limitations of surveillance systems. - Exclusion of BC level 2 cases without troponin elevation (except with definitive histopathology/CMR) may have led to underreporting; conversely, this approach aimed to reduce overreporting. - Incomplete etiologic workups (e.g., viral/autoimmune testing) in all cases, so alternative causes of myocarditis cannot be entirely excluded, though adjudication sought to rule them out. - Imaging data (echocardiography, CMR) were not available for all patients, limiting generalizability of imaging-based findings. - Lack of covariate data for the entire vaccinated population without VRM prevented identification of independent predictors for developing VRM at the population level; analyses of predictors were limited to severity among VRM cases. - Some cases occurred very early after vaccination (hours to 1 day); mechanisms remain uncertain, with hypersensitivity reaction proposed as a possibility.